Orthostastic intolerance is a dysfunction of the cardiovascular system that affects primarily young, healthy women. Diminished circulating blood volume and low peripheral resistance are primary mechanisms for orthostatic intolerance. Estrogen and progesterone modulate both plasma volume (PV) and peripheral vascular resistance (PVR). The purpose of this study is to compare PV regulation, PVR and orthostatic tolerance in women under four different hormonal conditions: when estrogen and progesterone are suppressed; when estrogen is elevated; when progesterone is elevated, and when progesterone and estrogen are elevated. The Specific Aims are: 1) To determine estrogen and progesterone modulation of extracellular fluid and protein distribution, and renal mechanisms controlling water retention. Plasma protein changes alter the colloid osmotic pressure gradient across capillaries and selectively enhance or reduce plasma volume. We hypothesize that estrogen acts on vessels to reduce vascular permeability to proteins, thereby reducing protein and fluid movement out of the vasculature and increasing PV. Moreover, we will test the hypothesis that estrogen and progesterone increase total extracellular fluid volume (ECFV) associated with renin-angiotensin-aldosterone system (RAAS)-mediated renal adjustments. Thus cardiovascular adjustments to postural changes may be improved when estrogen is elevated due to greater fluid retention and due to selective fluid retention in the plasma. We also hypothesize that PV expansion is the consequence of ECFV expansion when progesterone is increased concomitant with estrogen. High progesterone alone may reduce PV both by reducing colloid osmotic pressure gradient across capillaries and by attenuating aldosterone actions on the kidney, reducing water retention, and thus extracellular fluid and plasma volumes. 2) To test the hypothesis that estrogen-related reductions in PVR response to posture changes contribute to orthostatic intolerance in women, and progesterone antagonizes these estrogen mediated changes in PVR, helping to maintain orthostatic tolerance. These studies will define the impact of estrogen and progesterone on the interaction between blood volume and vascular resistance during orthostatic challenges, and thus may improve treatment of orthostatic intolerance in women. [unreadable] [unreadable]